The overall goal of our program is to develop more effective therapies for patients with mesothelioma using monoclonal antibodies direcetd to tumor differentiation antigens or growth factors. Our current studies are focused on using immunotherapy directed against two tumor targets mesothelin and Insulin Growth Factor 1 Receptor (IGF-1R). a. Laboratory studies and clinical trials of monoclonal antibodies targeting mesothelin. Mesothelin, a tumor differentiation antigen is expressed on normal mesothelial cells lining the pleura, pericardium and peritoneum but it is highly expressed in several human tumors especially mesothelioma, ovarian, lung and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. SS1P is a recombinant immunotoxin consisting of the anti-mesothelin Fv linked to a truncated form of the potent bacterial toxin, Pseudomonas exotoxin A. We have previously established the safety and maximum tolerated dose (MTD) of SS1P in phase I clinical trials. Our laboratory studies showing synergy between SS1P and chemotherapy has led to our on-going clinical trial of SS1P in combination with pemetrexed and cisplatin in chemo-nave patients with pleural mesothelioma. Preliminary results of this study show a very high response rate with 8 out of the 10 evaluable patients treated at the maximum tolerated dose (MTD) having partial responses. While the results of this trial are exciting we are also interested in increasing the efficacy of SS1P. Since SS1P is an immunogenic protein majority of patients develop neutralizing antibodies to it that limits treatment to 1 to 2 cycles. My laboratory in collaboration with the Pastan group and the laboratory Dr. Dan Fowler at the NCI have shown that treatment with pentostatin plus cyclophosphamide abrogates the generation of immune response to SS1P in immunocompetent mice. Based on these results we have just started a pilot study to see in patients if pentostatin plus cyclophosphamide can decrease the immunogenicity of SS1P in patients with chemo-refractory mesothelioma and allow repeated administration of SS1P. We have also completed the single arm phase II clinical trial of MORAb-009 with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma. This clinical trial has met its accrual goal with 89 patients enrolled and is awaiting data analysis. In addition to SS1P and MORAb-009 we are about to initiate a phase I clinical to determine the safety and MTD of the anti-mesothelin antibody drug conjugate BAY 94-9343, which consists of a humanized anti-mesothelin monoclonal antibody linked to the maytansinoid DM4. b. Laboratory studies and clinical trial of a monoclonal antibody targeting IGF-1R. Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that has proliferative and anti-apoptotic effects. Altered expression of the IGF-1 signaling cascade and increased activity of IGF-1R results in proliferation of several tumor types and may also contribute to resistance to anticancer therapies including cytotoxic chemotherapy and biologic therapies. The IGF-1R pathway is activated in malignant mesothelioma cell lines and tissues. Cixutumumab (IMC-A12) is a fully human monoclonal antibody to IGF-1R and blocks its interaction with its ligands IGF-1 and IGF-2. This leads to internalization and degradation of IGF-1R. My laboratory is currently studying IGF-1R as target for mesothelioma therapy using IMC-A12. We have established several early passage mesothelioma cell lines obtained from patients and are characterizing them for IGF-1R expression in detail including sites per cell. The anti-tumor activity of IMC-A12 is being evaluated using these and established mesothelioma cell lines as well as in-vivo studies against mesothelioma tumor xenografts. Our results show that the anti-tumor efficacy of cixutumumab including inhibition of IGF-IR downstream signaling is highly correlated with IGF-IR sites/cell. We have currently conducting a phase II clinical trial to test the efficacy of IMC-A12 in patients with malignant mesothelioma who have failed standard chemotherapy. Exploratory endpoints of this study include evaluation of tumor IGF-1R expression, correlation of tumor response with FDG-PET imaging and use of serum mesothelin as a marker of tumor response. This study opened in July 2010 has thus far 20 patients have been enrolled.